Scientists find "hidden" pre-cancer signs in advanced esophageal cancer patients

Scientists have found the strongest evidence to date that a condition known as Barrett's esophagus is the starting point for all cases of esophageal adenocarcinoma – the most common type of esophageal cancer in the developed world – even when telltale signs of this pre-cancerous stage are no longer visible.

The findings, published today in Nature Medicine, could help improve screening for and early detection of esophageal cancer, the sixth most deadly cancer, helping improve outcomes for the disease.

Cancer of the esophagus, including its most common form esophageal adenocarcinoma (OAC), is on the rise in western countries. It is difficult to treat because it is often caught at an advanced stage, when treatment options are limited.

Scientists and doctors have known for some time that the development of esophageal cancer is linked with Barrett's esophagus, which shows up in endoscopy as a pink patch in the surface of the esophagus. Barrett's esophagus affects around one out of every 100 to 200 people in the United Kingdom.

Between three and 13 people out of 100 with Barrett's esophagus will go on to develop esophageal adenocarcinoma in their lifetime. However, around half of OAC patients have no detectable Barrett's esophagus when their cancer is found, raising doubts about whether it is always the precursor.

Professor Rebecca Fitzgerald from the Li Ka Shing Early Cancer Institute at the University of Cambridge said: "Cancer generally takes many years to evolve, giving us a window of opportunity to catch it before if develops into a life-threatening condition. Screening and preventative strategies can have a massive impact on the number of people who die from cancer, but if the link between precancers and cancer is unproven or unclear, screening programs risk doing more harm than good."

To answer the question of whether Barrett's esophagus is a pre-requisite for OAC, researchers from Professor Fitzgerald and colleagues analyzed epidemiological and clinical data from 3,100 OAC patients undergoing surgery to remove their tumor or diseased tissue. Patients were recruited from 25 centers across the UK.

The team also analyzed whole genome sequencing data from 710 patients, which allows them to look at all of an individual's DNA, and whole exome sequencing from multiple samples taken from 87 patients, allowing them to understand how their tumors evolved and how different parts of the same cancer may differ genetically.

The researchers hypothesized that if OAC can arise through different routes – not always involving Barrett's esophagus – then genomic data and associated risk factors would differ between these two groups. Conversely, extensive overlap would strongly suggest that Barrett's esophagus plays a central role in OAC progression.

Just over a third of participants (35 %) had a diagnosis of Barrett's esophagus. However, the DNA, mutations, genomic patterns, and cellular 'identity' inside the cancers were essentially indistinguishable, regardless of whether doctors could identify Barrett's esophagus during endoscopy or in pathology samples.

The only major difference between cancers with or without visible Barrett's esophagus was the tumor stage – those patients without signs of Barrett's esophagus tended to have more advanced cancers. However, the team found biomarkers for Barrett's esophagus, such as the proteins TFF3 and REG4 present in the esophagus cells at all disease stages including before the cancer has developed. This suggests that the growing tumor can destroy the original Barrett's tissue, but importantly that proteins such as TFF3 and REG4 could be used to find individuals at future risk of esophageal cancer.

Dr Shahriar Zamani, joint first author from the Li Ka Shing Early Cancer Institute at Cambridge and now based at the National Institutes of Health in Bethesda, US, said: "We found no evidence for an alternative pathway to esophageal adenocarcinoma other than Barrett's esophagus. Because it seems to be the universal precursor, detecting Barrett's esophagus earlier could offer a clearer route to preventing esophageal cancer."

Dr Lianlian Wu, joint first author, also from the Li Ka Shing Early Cancer Institute, said: "What we need now are more sensitive, minimally invasive tests that identify people at risk based on molecular markers rather than relying solely on visible changes found during endoscopy."

The research was supported by Cancer Research UK and the Medical Research Council, with additional support by the National Institute for Health and Care Research (NIHR) Cambridge Biomedical Research Centre.

Dr Dani Skirrow, Research Information Manager at Cancer Research UK, said: "Detecting the earliest signs that cancer might develop gives us the opportunity to intervene and potentially prevent the disease.

This research helps to clarify how the most common type of esophageal cancer begins and, crucially, shows that the earliest signs are detectable even when doctors can't see them. This opens the door to future tests that look for molecular clues of hidden pre-cancerous changes, helping people understand their risk of esophageal cancer and get the necessary support to help keep the disease at bay."

Dr. Dani Skirrow, Research Information Manager, Cancer Research UK

Professor Fitzgerald is the Research Lead for Cambridge Cancer Research Hospital, a new hospital that will transform how we diagnose and treat cancer. She has led the development of a capsule sponge test to diagnose Barrett's esophagus, which can be easily administered at a GP surgery, speeding up diagnosis.

The University of Cambridge and Addenbrooke's Charitable Trust (ACT) are fundraising for Cambridge Cancer Research Hospital, where detecting cancer at its earliest stages will be a key goal. Set to be built on the Cambridge Biomedical Campus, the hospital will bring together clinical excellence from Addenbrooke's Hospital and world-leading researchers at the University of Cambridge. The research that takes place there promises to change the lives of cancer patients across the UK and beyond. Find out more here.